High expression of LncRNA HOTAIR is a risk factor for temozolomide resistance in glioblastoma via activation of the miR-214/β-catenin/MGMT pathway.
Humans
Temozolomide
/ pharmacology
RNA, Long Noncoding
/ genetics
Glioblastoma
/ genetics
Drug Resistance, Neoplasm
/ genetics
MicroRNAs
/ genetics
beta Catenin
/ metabolism
Cell Line, Tumor
Gene Expression Regulation, Neoplastic
/ drug effects
DNA Modification Methylases
/ metabolism
Tumor Suppressor Proteins
/ genetics
DNA Repair Enzymes
/ genetics
Antineoplastic Agents, Alkylating
/ pharmacology
Brain Neoplasms
/ genetics
Risk Factors
Wnt Signaling Pathway
/ drug effects
Apoptosis
/ drug effects
Methotrexate
Resistance
Temozolomide
lncRNA HOTAIR
Β-catenin
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
31 Oct 2024
31 Oct 2024
Historique:
received:
02
07
2024
accepted:
22
10
2024
medline:
1
11
2024
pubmed:
1
11
2024
entrez:
1
11
2024
Statut:
epublish
Résumé
HOX transcript antisense RNA (HOTAIR) is upregulated in glioblastoma (GBM) and associated with temozolomide (TMZ) resistance. However, the mechanisms underlying HOTAIR-mediated TMZ resistance remains poorly understood. HOTAIR expression in glioma-related public datasets and drug response estimation were analyzed using bioinformatics. These findings were verified by overexpressing HOTAIR in TMZ-sensitive U251 cells and/or silencing HOTAIR in resistant U251 cells (U251R). The cytotoxic effects were evaluated using cell viability assay and flow cytometry analysis of cell cycle and apoptosis. In this study, we found that HOTAIR was upregulated in TMZ-resistant GBM cell lines and patients with high HOTAIR expression responded poorly to TMZ therapy. HOTAIR knockdown restored TMZ sensitivity in U251R cells, while HOTAIR overexpression conferred TMZ resistance in U251 cells. Wnt/β-catenin signaling was enriched in patients with high HOTAIR expression; consistently, HOTAIR positively regulated β-catenin expression in U251 cells. Moreover, HOTAIR-mediated TMZ resistance was associated with increased MGMT protein level, which resulted from the HOTAIR/miR-214-3p/β-catenin network. Besides, GBM with high HOTAIR expression exhibited sensitivity to methotrexate. Methotrexate enhanced TMZ sensitivity in U251R cells, accompanied by reduced expression of HOTAIR and β-catenin. Thus, we conlcude that HOTAIR is a risk factor for TMZ resistance and methotrexate may represent a potential therapeutic drug for patients with high HOTAIR expression level.
Identifiants
pubmed: 39482401
doi: 10.1038/s41598-024-77348-z
pii: 10.1038/s41598-024-77348-z
doi:
Substances chimiques
Temozolomide
YF1K15M17Y
RNA, Long Noncoding
0
HOTAIR long untranslated RNA, human
0
MicroRNAs
0
beta Catenin
0
MGMT protein, human
EC 2.1.1.63
DNA Modification Methylases
EC 2.1.1.-
Tumor Suppressor Proteins
0
MIRN214 microRNA, human
0
DNA Repair Enzymes
EC 6.5.1.-
Antineoplastic Agents, Alkylating
0
CTNNB1 protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
26224Subventions
Organisme : Translational Medicine Research Fund of the Zhongnan Hospital of Wuhan University
ID : ZNLH201901
Informations de copyright
© 2024. The Author(s).
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